Rhodopsin mechanisms

Since the activation mechanism likely involves displacements of transmembrane helices relative to one another, the helix contacts illuminated by the crystal structure provide a wealth of new information relevant to rhodopsin mechanism. For example, the tilt and central location of TMlll indicates that it can pack against and articulate with TMll and VI, while TMVl is significantly kinked by the presence of Pro267 ° near its extracellular end. These helical interfaces and proline-induced kinks comprise important aspects of current hypotheses of receptor activation (HubbeU et al, 2003 Visiers et al, 2002). Interestingly, TMs 1, IV, and V also contain conserved prolines but are not kinked significantly. The extracellular loops and amino terminus were found to contain antiparaUel / strands, with a strand provided by ECLlf partially buried in the central pore where... 

Szundi I, Lewis J W and Kliger D S 1997 Deriving reaction mechanisms from kinetic spectroscopy. Application to late rhodopsin intermediates Blophys. J. 73 688-702... 

FIGURE 2.1 A side view of the structure of the prototype G-protein-coupled, 7TM receptor rhodopsin. The x-ray structure of bovine rhodopsin is shown with horizontal gray lines, indicating the limits of the cellular lipid membrane. The retinal ligand is shown in a space-filling model as the cloud in the middle of the structure. The seven transmembrane (7TM) helices are shown in solid ribbon form. Note that TM-III is rather tilted (see TM-III at the extracellular and intracellular end of the helix) and that kinks are present in several of the other helices, such as TM-V (to the left), TM-VI (in front of the retinal), and TM-VII. In all of these cases, these kinks are due to the presence of a well-conserved proline residue, which creates a weak point in the helical structure. These kinks are believed to be of functional importance in the activation mechanism for 7TM receptors in general. Also note the amphipathic helix-VIII which is located parallel to the membrane at the membrane interface. 

The analysis of CD and absorption data has been used since 1974, mainly by Nakanishi and his coworkers, to study the structure of the rhodopsins, pigments involved in the mechanism of vision, and of their chromophores50. 

Bleached rhodopsin must be regenerated to maintain normal vision. Regeneration occurs by several mechanisms. The major pathway occurs in the retinal pigmented... 

Intriguingly, the conical intersection model also suggests that E,Z-isomerization of acyclic dienes might be accompanied by conformational interconversion about the central bond, reminiscent of the so-called Hula-Twist mechanism for the efficient ,Z-photo-isomerization of the visual pigment rhodopsin in its rigid, natural protein environment101. A study of the photochemistry of deuterium-labelled 2,3-dimethyl-l,3-butadiene (23-d2) in low temperature matrices (vide infra) found no evidence for such a mechanism in aliphatic diene E,Z -photoisomerizations102. On the other hand, Fuss and coworkers have recently reported results consistent with the operation of this mechanism in the E,Z-photoisomerization of previtamin D3 (vide infra)103. 

The study of the mechanism of vision in vertebrates 23>24) has progressed to the point where the first consequence of photon absorption has been described as an activation of the isomerization of the 11 -cis retinal chromophore of rhodopsin to all-trans. That triggers a complex sequence of reactions leading to the mysterious inside of the brain. Brrr, I had better get back — it looks dark in there. But the brain can generate sensations of light. Maybe, one day, we will be able to see enough to understand, but we ll go back just the same to a safer subject. 

Dean, K.R. Akhtar, M. Novel mechanism for the activation of rhodopsin kinase Implications for other G protein-coupled receptor kinases (GRK s). Biochemistry, 35, 6164-6172 (1996)... 

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